2015 Antineoplastics

B. PYRIMIDINE ANALOGUES : 5-FLUOROURACIL, CAPECITABINE

5FU metabolismPharmacokinetics

5-FLUOROURACIL

  • must be activated by entering the pyrimidine synthesis pathway
    • although 5-FU can enter the pathway at 3 different places, two key entry points occur before the conversion of UMP to UDP, which is catalyzed by pyrimidine monophosphate kinase (reductions in PMK activity decrease the concentration of metabolites available to block thymidylate synthase; see resistance)

  • given IV
    • limited oral bioavailability because gut mucosa has high concentrations of dihydropyrimidine dehydrogenase

  • significant metabolic degradation occurs (~80% of the drug is eliminated by hepatic metabolism and 20% by renal excretion)
    • many other tissues also degrade 5-FU
    • inherited deficiency of dihydropyrimidine dehydrogenase leads to greatly increased drug sensitivity (~8% of US population)
CAPECITABINE
  • oral administration

  • converted to 5-FU via a 3 step activation process
    • first two steps occur in the liver
    • the last step is carried out by the enzyme thymidine phosphorylase, which is overexpressed in a large number of tumours (~3X compared to normal tissue) which gives CAPECITABINE greater selective toxicity than 5-FU
Email: Dr. Janet Fitzakerley | ©2015 University of Minnesota Medical School Duluth | Last modified: 4-may-15 9:41 PM